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Biomedical subjects

N J Wareham

Publications and source records attributed to N J Wareham.

At least 55 records · Page 3Linked to original sources

Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study.

We previously identified a hormone sensitive lipase (HSL) promoter variant, -60C>G, which in vitro exhibits 40% reduced promoter activity. In this study we examined the effect of the -60C>G on glycemic and lipid measures in the population based Ely study of metabolic function and insulin resistance in 218 middle-aged men and 276 middle-aged women. Adipose tissue HSL is the rate-limiting step in triglyceride lipolysis, generating free fatty acids for energy utilization. HSL is also expressed in pancreatic beta-cells where its activity therefore may affect insulin secretion. In the women, carriers of the HSL -60G allele had significantly lower fasting insulin levels (P=0.0005) and a lower total area under the curve for insulin during the oral glucose tolerance test (P=0.005). There was no demonstrable association in men with these measures of insulin sensitivity but carriers of the -60G allele had significantly lower fasting non-esterified fatty acid (NEFA) levels (P=0.025) and higher low density lipoprotein cholesterol levels (P=0.02) than men who were non-carriers. This study provides additional evidence for a role for HSL in the development of insulin resistance, from which carriers of the -60G allele, associated here with markers of insulin sensitivity in women, and with lower NEFA levels in men, might be protected.

Diabetes Mellitus, Type 2↗

Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction.

Although familial clustering has been described, few studies have quantified the risk of airflow obstruction in siblings of patients with chronic obstructive pulmonary disease (COPD). One hundred fifty-two subjects with airflow obstruction and a low gas transfer factor (but without PiZ alpha(1)-antitrypsin deficiency) were identified and 150 were enrolled in the study. Complete data were obtained from 173 of 221 siblings of these subjects. Forty-four of 126 current or ex-smoking siblings had airflow obstruction (FEV(1)/FVC < 0.7) and 36 also had a FEV(1) < 80% predicted, in keeping with COPD. One hundred eleven current or ex-smoking siblings were matched for age, sex, and smoking history with 419 subjects, without a known family history of COPD, from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort. The prevalence of COPD was much lower in the EPIC group (9.3%) when compared with the siblings (31.5%; odds ratio, 4.70; 95% confidence interval, 2.63 to 8.41). The odds ratio for COPD in siblings with less than a 30 pack-year smoking history was 5.39 (95% confidence interval, 2.49 to 11.67) when compared with matched control subjects. Taken together these results demonstrate a significant familial risk of airflow obstruction in smoking siblings of patients with severe COPD.

Aged↗

Patterns of physical activity and ultrasound attenuation by heel bone among Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): population based study.

OBJECTIVES: To study associations between patterns of physical activity and ultrasound attenuation by the heel bone in men and women. DESIGN: Cross sectional, population based study. SETTING: Norfolk. PARTICIPANTS: 2296 men and 2914 women aged 45-74 registered with general practices participating in European Prospective Investigation into Cancer (EPIC Norfolk). RESULTS: Self reported time spent in high impact physical activity was strongly and positively associated with ultrasound attenuation by the heel bone, independently of age, weight, and other confounding factors. Men who reported participating in >/=2 hours/week of high impact activity had 8.44 dB/MHz (95% confidence interval 4.49 to 12.40) or 9.5%, higher ultrasound attenuation than men who reported no activity of this type. In women, the difference in ultrasound attenuation between those reporting any high impact activity and those reporting none was 2.41 dB/MHz (0.45 to 4.37) or 3.4% higher. In women this effect was similar in size to that of an age difference of four years. Moderate impact activity had no effect. However, climbing stairs was strongly independently associated with ultrasound attenuation in women (0.64 dB/MHz (0.19 to 1.09) for each additional five flights of stairs). There was a significant negative association in women between time spent watching television or video and heel bone ultrasound attenuation, which decreased by 0.08 dB/MHz (0.02 to 0.14) for each additional hour of viewing a week. CONCLUSIONS: High impact physical activity is independently associated with ultrasound attenuation by the heel bone in men and women. As low ultrasound attenuation has been shown to predict increased risk of hip fracture, interventions to promote participation in high impact activities may help preserve bone density and reduce the risk of fracture. However, in older people such interventions may be inappropriate as they could increase the likelihood of falls.

Age Factors↗

Fruit and vegetable intake and population glycosylated haemoglobin levels: the EPIC-Norfolk Study.

OBJECTIVE: To investigate whether self-reported frequency of fruit and vegetable consumption was associated with HbA(1C) levels in individuals not known to have diabetes, and what dietary and lifestyle factors might explain this association. DESIGN: Cross-sectional study. SETTING: The EPIC-Norfolk Study, a population-based cohort study of diet and chronic disease. SUBJECTS AND METHODS: A total of 2678 men and 3318 women (45-74 y) not known to have diabetes reported weekly consumption of fruit, green leafy vegetables and other vegetables. RESULTS: Among men, 274 (10.2%) reported seldom or never eating fruit and 127 (4.7%) seldom or never eating green leafy vegetables. Corresponding numbers in women were 157 (4.7%) and 92 (2.8%), respectively. Participants who reported never or seldom having both fruit and green leafy vegetables had higher mean (s.d.) HbA(1C) measurements (5.43% (0.71)) than those who reported more frequent consumption (5.34% (0.67); P=0.046). Differences by category of fruit or green leafy vegetable consumption were not substantially changed after adjustment for saturated fat, dietary fibre and plasma vitamin C. CONCLUSION: These findings support the hypothesis that high intake of fruit and green leafy vegetables may influence glucose metabolism independent of dietary fibre or vitamin C alone and that increased consumption may contribute to the prevention of diabetes.

Aged↗

Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population.

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contributes to human obesity. SUBJECTS: Ninety-one obese children (BMI>4 standard deviations from age related mean) and 419 Caucasian adults from the Isle of Ely Study. DESIGN: Single strand conformation polymorphism (SSCP) analysis was used to scan the coding region of the UCP3 gene in 91 severely obese children. A common polymorphism identified in this gene (c-55t) has been shown to associate with lower UCP3 mRNA expression. Polymerase chain reaction-based forced restriction digestion was used to detect this allele in Caucasian adults. Multiple regression analysis was used to determine associations between the c-55t genotype and anthropometric, energetic and biochemical indices relevant to obesity. MEASUREMENTS: For the obese children, SSCP analysis and sequencing of variants were carried out. For the Isle of Ely Study, c-55t genotype and anthropometric (body mass index, waist-hip ratio, percentage body fat), energetic (dietary fat intake, physical activity index, adjusted metabolic rate, maximum oxygen consumption) and biochemical indices (pre- and post-glucose challenge plasma triglycerides, non-esterified fatty acids, insulin and glucose) were determined. RESULTS: A previously reported missense mutation (V102I) was detected in a single obese Afro-Carribean child. Twenty-one percent of the genes examined in the Isle of Ely study carried the c-55t promoter variant. Age-adjusted body mass index (BMI) was significantly (P=0.0037) lower in carriers of this variant. CONCLUSION: Mutations in the coding sequence of UCP3 are unlikely to be a common monogenic cause of severe human obesity. In a Caucasian population the UCP3 c-55t polymorphism is negatively associated with BMI.

Adolescent↗

Is the association between dietary fat intake and insulin resistance modified by physical activity?

The rising prevalence of type 2 diabetes, a condition associated with insulin resistance, is commonly attributed to changes in dietary patterns and physical activity levels in susceptible populations. However, few studies have described the independent effects of dietary intake and physical activity on the degree of insulin sensitivity within populations or examined the possibility of interactions between dietary factors and physical activity. This study was undertaken to describe the relationship between the quantity and pattern of dietary fat intake on fasting insulin levels (a marker of insulin sensitivity) and to investigate whether the association was modified by physical activity. A cross-sectional study of 815 nondiabetic men and women (30 to 71 years) recruited from a population-based sampling frame was undertaken. Diet was characterized using a semiquantitative food frequency questionnaire. Physical activity level (PAL), the ratio of total energy expenditure to basal metabolic rate, was estimated using individually calibrated heart rate monitoring, a method previously shown to be an objective and valid method for assessing total energy expenditure. In a linear regression model adjusted for total energy intake, total fat intake bordered on a significant association with fasting insulin (b = 0.000081; P =.058), and the polyunsaturated to saturated fat ratio (P:S ratio) of the diet was negatively associated with fasting insulin concentration (b = -0.37, P <.001). A negative association was observed between the PAL and fasting insulin (b = -0.12, P =.025). The association of the P:S ratio and PAL with fasting insulin remained significant when adjusted for each other and for total fat, total energy intake, body mass index (BMI), waist-to-hip ratio (WHR), age, sex, family history of diabetes, smoking status, and alcohol intake (P:S ratio, b = -0.24, P =.003; PAL, b = -0.13; P =.007). The association with total fat intake was no longer significant in this multivariate model (b = 6.7 x 10(-6); P =.858). There was no evidence for an interaction between total dietary fat intake and PAL (b = -0.000048; P =.243) or between the P:S ratio and PAL (b = -0.013; P =.949). These data demonstrate an independent association between the P:S ratio of the diet, the overall level of physical activity, and the fasting insulin concentration, a marker of insulin sensitivity. There was no evidence that the association between dietary fat intake and insulin resistance was modified by physical activity. The findings provide further support for efforts to promote increases in overall physical activity and modifications in the pattern of dietary fat intake in the whole population.

Adult↗

Physical activity patterns in a nationally representative sample of adults in Ireland.

OBJECTIVE: To evaluate habitual levels of physical activity in a nationally representative sample of adults in Ireland. DESIGN: Cross-sectional survey using a self-administered questionnaire. Usual levels of work, recreational and household activities were evaluated in relation to anthropometric, demographic and socio-economic characteristics. The amount and intensity of all activities were quantified by assigning metabolic equivalents (METS) to each activity. SETTING: Republic of Ireland and Northern Ireland, 1997-1999. SUBJECTS: Random sample of 1379 adults aged 18-64 years. RESULTS: Men were approximately twice as active in work and recreational activity (139.7 +/- 83.9 METS) as women (68.5 +/- 49.8 METS; P<0.001) but women were three times more active in household tasks (65.9 +/- 58.7 METS vs. 22.6 +/- 24.6 METS; P<0.001). Overall levels of physical activity declined with increasing age, particularly leisure activity in men. In women the decline in work activity was offset by spending more time in household pursuits. Twenty-five per cent of the subjects were extremely overweight (body mass index (BMI>28 kg m(-2)) or obese (BMI >30 kg m (-2)). Fewer obese subjects reported higher levels of work and leisure activities. However, a higher percentage of obese women reported participation in the higher levels of household activities. Participation rates in recreational activities were low. Walking was the most important leisure activity of both men (41%) and women (60%). In terms of hours per week spent in vigorous physical activity, men were more active than women, professional and skilled non-manual women were more active than women in other social classes, and younger subjects (aged 18-35 years) were more active than older subjects. CONCLUSIONS: The holistic approach used in the assessment of physical activity in this study has revealed important and subtle differences in the activity patterns of men and women. Failure to fully characterise the respective activity patterns of men and women could lead to ill-informed public health policy aimed at promoting and sustaining lifetime habits of physical activity. The results suggest that simple population-focused programmes to promote physical activity are unlikely to offer the same chance of long-term success as more sensitive and individualised strategies.

Adolescent↗

Low faecal elastase 1 concentrations in type 2 diabetes mellitus.

BACKGROUND: Previous studies have suggested an association between impaired pancreatic exocrine function and diabetes, but the evidence is weak because the invasive nature of the tests used to define exocrine function has led to small studies on selected patients. The availability of faecal elastase 1 as a non-invasive test has aided the detection of impaired exocrine function in population studies. We describe the association between levels of faecal elastase 1 and Type 2 diabetes. METHODS: 544 Type 2 diabetic patients (age: 63 +/- 8 years) were randomly selected from local diabetes registers in Cambridgeshire, UK and individually matched for age, sex and practice to 544 controls in whom diabetes was excluded by HbA1c measurement. RESULTS: Faecal elastase 1 concentrations were significantly lower in cases than controls (median: cases 308 microg/g; controls 418 microg/g; P < 0.01). Low levels of faecal elastase 1 (< 100 microg/g) were found in 11.9% of cases and 3.7% of controls (age-sex-adjusted odds ratio; 95% CI: 3.6; 2.2-6.2). After adjustment for potential confounding factors, the OR was 4.5 (2.6-8.3). Among patients with diabetes, poor glycaemic control (HbA1c > or = 7%) was associated with a higher risk of low elastase 1 level (OR 5.6; 1.5-37). No significant association was found with diabetes duration, peripheral neuropathy, alcohol intake, or prior gastrointestinal diseases. CONCLUSIONS: Faecal elastase 1 concentrations are lower in Type 2 diabetic patients than in non-diabetic controls, suggesting the co-existence of diabetes and impaired pancreatic exocrine function. Among the diabetic patients, the risk of having low elastase 1 levels was associated with glycaemic control.

Aged↗

Cigarette smoking and glycaemia: the EPIC-Norfolk Study. European Prospective Investigation into Cancer.

BACKGROUND: Previous prospective studies have suggested that cigarette smoking may be associated with an increased risk of type 2 diabetes, but the possibility of confounding, particularly by dietary factors has not been fully examined. METHODS: Cross-sectional analysis of the association between cigarette smoking and HbA(1C), a marker of long-term glucose homeostasis in 2704 men and 3385 women, aged 45--74 years who were recruited to a population-based study of diet and chronic disease. RESULTS: Twelve per cent of men and 11% of women reported being current smokers. Mean HbA(1C) was lowest in never smokers, intermediate in former smokers and highest in current smokers. There was a dose-response relationship between HbA(1C) levels and number of cigarettes smoked per day and a positive association with total smoking exposure as measured by pack-years. The unadjusted increase in HbA(1C) for 20 pack-years of smoking was 0.12% (95% CI : 0.09--0.16) in men and 0.12% (95% CI : 0.08--0.17) in women. After adjustment for possible confounders including dietary variables, the values were 0.08% (95% CI : 0.04--0.12) and 0.07% (95% CI : 0.02--0.12) for men and women, respectively. Mean HbA(1C) was inversely related to time since quitting smoking in men. CONCLUSIONS: These results add support to the hypothesis that smoking has long-term effects on glucose homeostasis, an association that cannot be explained by confounding by dietary factors as measured in this study.

Aged↗

Sample size determination for studies of gene-environment interaction.

BACKGROUND: The search for interaction effects is common in epidemiological studies, but the power of such studies is a major concern. This is a practical issue as many future studies will wish to investigate potential gene-gene and gene-environment interactions and therefore need to be planned on the basis of appropriate sample size calculations. METHODS: The underlying model considered in this paper is a simple linear regression and relating a continuous outcome to a continuously distributed exposure variable. RESULTS: The slope of the regression line is taken to be dependent on genotype, and the ratio of the slopes for each genotype is considered as the interaction parameter. Sample size is affected by the allele frequency and whether the genetic model is dominant or recessive. It is also critically dependent upon the size of the association between exposure and outcome, and the strength of the interaction term. The link between these determinants is graphically displayed to allow sample size and power to be estimated. An example of the analysis of the association between physical activity and glucose intolerance demonstrates how information from previous studies can be used to determine the sample size required to examine gene-environment interactions. CONCLUSIONS: The formulae allowing the computation of the sample size required to study the interaction between a continuous environmental exposure and a genetic factor on a continuous outcome variable should have a practical utility in assisting the design of studies of appropriate power.

Effect Modifier, Epidemiologic↗

Estimating energy expenditure by heart-rate monitoring without individual calibration.

UNLABELLED: Heart rate monitoring has been shown to be a valid method for measuring free-living energy expenditure at the group level, but its use in large-scale studies is limited by the need for an individual calibration of the relationship between heart rate and energy expenditure. PURPOSE: To determine whether energy expenditure can be estimated from heart rate monitoring without individual calibration in epidemiological studies. METHODS: Our previously validated heart rate monitoring method relies on measuring individual calibration parameters obtained from resting energy expenditure and the regression line between energy expenditure and heart rate during exercise. We developed prediction equations for these parameters using easily measured variables in a population-based study of 789 individuals. The predictive ability of these parameters was tested in a separate population-based sample (N = 97). RESULTS: Physical activity level (PAL = total energy expenditure/basal metabolic rate) using the four estimated parameters was correlated with PAL using the measured parameters (r = 0.82, P < 0.01). Comparison of measured and estimated PAL showed that 97.9% of the scores were placed in the same or adjacent quartile. CONCLUSION: A combination of simple measurements and heart rate monitoring produces estimates of energy expenditure that are highly correlated with those obtained using full individual calibration. This simplification of the heart rate monitoring method could extend its use in ranking individuals in epidemiological studies.

Calibration↗

The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity.

The lipolytic effects of catecholamines are mediated through members of the beta(2)-adrenergic receptor (BAR-2) family. Previous studies have suggested that genetic variants in the BAR-2 gene may be associated with obesity in some populations. To our knowledge, no studies have directly examined the effects of this polymorphism on circulating nonesterified fatty acid (NEFA) levels. To explore this issue further, a cohort of 604 Caucasian individuals (aged 40-65 yr) was genotyped for a common polymorphism in the BAR-2 gene (Gly16Arg), and the relationships between genotype, body mass index (BMI), NEFA, and lipid levels were examined. Women bearing the Arg16 allele had higher BMI values (P < 0.01) than Gly16Gly women. Women carriers of the Arg16Arg genotype had lower fasting plasma NEFAs (P < 0.01) and greater suppression of NEFAs (P < 0.01) after an oral glucose load than women bearing the Gly16 allele. In multivariate analysis after adjustment for age, sex, and smoking status, the interaction between the BAR-2 genotype and BMI in determining fasting NEFA concentrations was statistically significant (P < 0.05). The availability of objective measures of total energy expenditure in this population permitted the further examination of interactions, particularly that between genotype and physical activity. In the population as a whole, after adjustment for confounding by age, smoking, and BMI, the effect of the Arg16Arg genotype on the suppression of NEFA levels was modified by physical activity level (P for interaction <0.05). These data suggest the existence in this population of a gene-physical activity interaction on NEFA levels.

Adult↗

Evidence for gene-nutrient interaction at the PPARgamma locus.

The importance of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) in regulating insulin resistance and blood pressure has been demonstrated in families with loss of function mutations. Gain of function mutations has been associated with severe obesity. However, previous population studies of the common variant Pro12Ala have produced conflicting results. As it is likely that the natural ligands for this receptor may include fatty acids, we hypothesized that the effect of this common variant may be altered by the character of the diet, particularly the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio). We studied 592 nondiabetic participants in an ongoing population-based cohort study who were genotyped for the Pro12Ala polymorphism in the PPAR gamma2 isoform. As the Ala homozygotes were uncommon (2.0%), all analyses were conducted comparing Pro homozygotes (79.1%) to Ala allele carriers. There was no difference in fasting insulin concentration or BMI between Ala allele carriers and Pro homozygotes. The fasting insulin concentration was negatively associated with the P:S ratio (P = 0.0119) after adjustment for age and sex, and a strong interaction was evident between the P:S ratio and the Pro12Ala polymorphism for both BMI (P = 0.0038) and fasting insulin (P = 0.0097). The data suggest that when the dietary P:S ratio is low, the BMI in Ala carriers is greater than that in Pro homozygotes, but when the dietary ratio is high, the opposite is seen. This gene-nutrient interaction emphasizes the difficulty of examining the effect of common polymorphisms in the absence of data on nongenetic exposures, and may explain the heterogeneity of findings in previous studies.

Adult↗

Do different dimensions of the metabolic syndrome change together over time? Evidence supporting obesity as the central feature.

OBJECTIVE: The metabolic syndrome is a loosely defined cluster of cardiovascular risk factors including low HDL cholesterol, hypertriglyceridemia, glucose intolerance, and hypertension. Evidence for inclusion of these features in the syndrome has mostly come from cross-sectional studies, and a few studies have examined how the various factors change together over time. RESEARCH DESIGN AND METHODS: We conducted a prospective population-based cohort study of 937 individuals aged 40-65 years who underwent oral glucose tolerance testing on two occasions at 4.5-year intervals. Changes in the components of the metabolic syndrome were analyzed by principal component analysis in the entire population and in a subgroup of 471 individuals who did not receive pharmaceutical therapy for hypertension and dyslipidemia. RESULTS: Principal component analysis identified three independent factors in men: a blood pressure factor (systolic and diastolic blood pressure and BMI), a glucose factor (fasting and 120-min postload glucose, BMI, waist-to-hip ratio [WHR], and fasting insulin level), and a lipid factor (triglycerides and HDL cholesterol, BMI, WHR, and fasting insulin level). In women, an additional factor was identified, which included BMI, WHR, fasting insulin, and triglycerides. Analysis of the contribution of these variables to the different subdimensions indicated that BMI was the central feature of the syndrome in both sexes. CONCLUSIONS: This analysis of change in the features of the metabolic syndrome over time provides evidence of the fundamental importance of obesity in the origin of this disorder.

Adult↗

Fat consumption and HbA(1c) levels: the EPIC-Norfolk study.

OBJECTIVE: To describe the relationship between total dietary fat and the pattern of fat intake and HbA(1c). RESEARCH DESIGN AND METHODS: In this cross-sectional study, 2,759 men and 3,464 women (40-78 years of age) without a previous diagnosis of type 2 diabetes were recruited from a population-based sampling frame. Diet was assessed using a self-reported semiquantitative food frequency questionnaire. RESULTS: The HbA(1c) level was negatively associated with the polyunsaturated fat-to-saturated fat ratio (P:S ratio) of the diet (beta = -0.0338 HbA(1c)% per SD change in P:S ratio; P < 0.001) and positively associated with the total level of fat intake (beta = 0.0620 HbA(1c)% per SD change in total fat intake; P < 0.001), adjusted for age and total energy intake. The associations remained significant when adjusted for each other and for total energy, protein, age, sex, family history of diabetes, BMI, waist-to-hip ratio, physical activity, and smoking (for P:S ratio, beta = -0.0200 HbA(1c)% per SD change in P:S ratio, P = 0.013; for total fat, beta = 0.420% HbA(1c)% per SD change in total fat intake, P < 0.001). The benefits from a high P:S ratio were attributed to a lower saturated fat intake. CONCLUSIONS: These findings demonstrate independent associations between HbA(1c) concentration across the normal range of HbA(1c) and both total fat intake and the pattern of dietary fat intake. They provide further support to efforts promoting modifications in the intake of dietary fat.

Adult↗

Glucose intolerance and physical inactivity: the relative importance of low habitual energy expenditure and cardiorespiratory fitness.

Glucose intolerance and diabetes mellitus are associated with physical inactivity, but it is unclear whether preventive interventions should aim at increasing overall energy expenditure or increasing participation in vigorous, fitness-enhancing activities. Studies aimed at separating and quantifying the effects of these two dimensions of physical activity should use well-validated measurement instruments and employ a study design in which the bivariate error structure of these instruments is determined. In the Isle of Ely Study (Cambridgeshire, United Kingdom), 775 individuals aged 45-70 years in 1994-1997 completed a glucose tolerance test and assessment of 4-day physical activity level (total energy expenditure/basal metabolic rate) by heart rate monitoring, a technique that has been validated against doubly labeled water and whole-body calorimetry. Cardiorespiratory fitness (maximum oxygen uptake (VO2max) per kg)) was measured in a submaximal test. To correct for measurement error, the authors had 190 individuals repeat both tests on three occasions at 4-month intervals. Two-hour glucose level was negatively correlated with physical activity level (men: r = -0.22, p < 0.001; women: r = -0.11, p < 0.05) and VO2max per kg (men: r = -0.18, p < 0.01; women: r = -0.19, p < 0.001) and was positively correlated with age and obesity. The model incorporating bivariate adjustment for measurement error showed that energy expenditure had a major effect on glucose tolerance, but there was less of an effect for cardiorespiratory fitness. These data provide support for public health strategies aimed at increasing overall energy expenditure.

Aged↗